Frank DeSimone was born in 1909 in Pueblo, Colorado.[2] As a child his family moved to California. Desimone graduated from the University of Southern California Law School[3] and became a lawyer in May 1933. Soon after he turned to a life in crime. DeSimone was involved in one of the botched assassination attempts on Mickey Cohen.[4]Jimmy Fratianno signaled DeSimone after a meeting with Cohen and DeSimone pulled up in a car with Frank Bompensiero, Leo Moceri, and another armed man. By the time they got past Cohen's bodyguards, Cohen escaped. With a job as an attorney, DeSimone was able to avoid police scrutiny. His lawyer career was no front job however. In the 1940s and 1950s DeSimone served as lawyer for mobsters such as Jimmy Fratianno and Johnny Roselli as well as providing legal aid to others.[5]

After Jack Dragna died of a heart attack in 1956, DeSimone was elected the third official Boss of the Los Angeles crime family. Jimmy Fratianno believed he had rigged the election and transferred to the Chicago Outfit afterwards. According to an informant shortly after he became boss, DeSimone supposedly raped the wife of his underboss, Girolamo "Momo" Adamo, in front of her husband. The humiliated "Momo" later shot his wife and committed suicide in their San Diego home. Marie Adamo survived her wounds and later married Frank Bompensiero. It is uncertain if DeSimone actually committed the actions that caused "Momo" to kill himself. By all accounts DeSimone was a straight laced and sober character. One of his first acts as boss was attending the 1957 Appalachian mob convention along with Simone Scozzari. When the conference was raided by law enforcement, DeSimone was outed as a mobster, and his underboss was deported to Italy for being an illegal immigrant.

Frank DeSimone is accused of ruining the Los Angeles family's reputation and integrity. Nonetheless, DeSimone was featured in Look Magazine in 1965 as one of the decade's notable figures in organized crime; DeSimone sued the magazine for libel.[citation needed]Jimmy Fratianno also blamed DeSimone in 1953 for having been sent to Folsom prison on a six-year extortion conviction, after dealing with con-artists James B. Modica (a man who 'bumped' slot machines and liquor store owners in Tarzana) and Frank Raspona. Fratianno accused DeSimone of ruining his case by not recording one of the defendants key witnesses who skipped town before being able to take the stand. DeSimone was later disbarred because of his criminal activities.

In the 1960s, Joseph Bonanno, in a plot to take over The Commission, plotted the murder of Mafia Bosses Thomas Lucchese, Carlo Gambino, and Stefano Magaddino, and added DeSimone to the list for good measure.[6] Although never carried out, DeSimone didn't learn about that plan until after it was thwarted. This caused DeSimone to become very paranoid. During the later part of his life he never went out during night.